EP1005453B1 - Substituierte benzolverbindungen als antiproliferative mittel - Google Patents
Substituierte benzolverbindungen als antiproliferative mittel Download PDFInfo
- Publication number
- EP1005453B1 EP1005453B1 EP98939384A EP98939384A EP1005453B1 EP 1005453 B1 EP1005453 B1 EP 1005453B1 EP 98939384 A EP98939384 A EP 98939384A EP 98939384 A EP98939384 A EP 98939384A EP 1005453 B1 EP1005453 B1 EP 1005453B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- aminosulfonyl
- methoxyphenyl
- alkyl
- ocf
- benzene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 18
- 239000003795 chemical substances by application Substances 0.000 title abstract description 9
- 230000001028 anti-proliverative effect Effects 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 120
- 239000000203 mixture Substances 0.000 claims abstract description 43
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 8
- 201000011510 cancer Diseases 0.000 claims abstract description 8
- 208000015181 infectious disease Diseases 0.000 claims abstract description 4
- 208000037803 restenosis Diseases 0.000 claims abstract description 4
- 230000002792 vascular Effects 0.000 claims abstract description 3
- -1 N((C1-C6)alkyl)2 Chemical group 0.000 claims description 56
- 229910052801 chlorine Inorganic materials 0.000 claims description 38
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 37
- 229910052794 bromium Inorganic materials 0.000 claims description 32
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 30
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 27
- 229910052731 fluorine Inorganic materials 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 150000002367 halogens Chemical group 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- 230000004663 cell proliferation Effects 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 229940127089 cytotoxic agent Drugs 0.000 claims description 5
- 230000002062 proliferating effect Effects 0.000 claims description 5
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical group O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229940002612 prodrug Drugs 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 230000000973 chemotherapeutic effect Effects 0.000 claims description 2
- 239000002254 cytotoxic agent Substances 0.000 claims description 2
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 2
- 230000008685 targeting Effects 0.000 claims description 2
- 244000005700 microbiome Species 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 22
- 238000011282 treatment Methods 0.000 abstract description 8
- 125000003118 aryl group Chemical group 0.000 abstract description 5
- 239000013543 active substance Substances 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 2
- 150000002611 lead compounds Chemical class 0.000 abstract description 2
- 239000002831 pharmacologic agent Substances 0.000 abstract description 2
- 201000001320 Atherosclerosis Diseases 0.000 abstract 1
- 208000035150 Hypercholesterolemia Diseases 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- 239000000460 chlorine Substances 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- RRONENSZKCGROA-UHFFFAOYSA-N 4-fluoro-3-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC(S(Cl)(=O)=O)=CC=C1F RRONENSZKCGROA-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- OQUWAOHSHWXMPX-UHFFFAOYSA-N 2-bromo-3,4,5-trifluoro-n-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=CC(F)=C(F)C(F)=C1Br OQUWAOHSHWXMPX-UHFFFAOYSA-N 0.000 description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- HIPCPVSKULEHBJ-UHFFFAOYSA-N 2-bromo-3,4,5-trifluoro-n-(3-hydroxy-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(O)C(OC)=CC=C1NS(=O)(=O)C1=CC(F)=C(F)C(F)=C1Br HIPCPVSKULEHBJ-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 7
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- FTIFAPZODKUUQX-UHFFFAOYSA-N 5-bromo-2,3,4-trifluoro-n-(3-hydroxy-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(O)C(OC)=CC=C1NS(=O)(=O)C1=CC(Br)=C(F)C(F)=C1F FTIFAPZODKUUQX-UHFFFAOYSA-N 0.000 description 6
- RCTCBSDWAUCMEI-UHFFFAOYSA-N 5-bromo-2,3,4-trifluoro-n-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=CC(Br)=C(F)C(F)=C1F RCTCBSDWAUCMEI-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 125000004404 heteroalkyl group Chemical group 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- IAPZMOXNDIVGNQ-UHFFFAOYSA-N 3-bromo-2,4,5,6-tetrafluoro-n-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(F)C(Br)=C1F IAPZMOXNDIVGNQ-UHFFFAOYSA-N 0.000 description 5
- BLQFHJKRTDIZLX-UHFFFAOYSA-N 5-amino-2-methoxyphenol Chemical compound COC1=CC=C(N)C=C1O BLQFHJKRTDIZLX-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical class ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 5
- XFTDZYFHXRZLEF-UHFFFAOYSA-N 2,3,4-trifluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C(F)=C1F XFTDZYFHXRZLEF-UHFFFAOYSA-N 0.000 description 4
- IAYLRIOAUQKCBY-UHFFFAOYSA-N 2-bromo-3,4,5,6-tetrafluoro-n-(3-hydroxy-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(O)C(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(F)C(F)=C1Br IAYLRIOAUQKCBY-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- 150000001491 aromatic compounds Chemical class 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 230000002285 radioactive effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 0 *c(cc1*)c(*)c(*)c1S(Cl)(=O)=O Chemical compound *c(cc1*)c(*)c(*)c1S(Cl)(=O)=O 0.000 description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 3
- COVHFELBSZZSOI-UHFFFAOYSA-N 2,3,4,5-tetrafluoro-n-(3-hydroxy-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(O)C(OC)=CC=C1NS(=O)(=O)C1=CC(F)=C(F)C(F)=C1F COVHFELBSZZSOI-UHFFFAOYSA-N 0.000 description 3
- QITZCKFTLJUUKY-UHFFFAOYSA-N 2,3,4,5-tetrafluoro-n-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=CC(F)=C(F)C(F)=C1F QITZCKFTLJUUKY-UHFFFAOYSA-N 0.000 description 3
- CUBSXTAOVAEONH-UHFFFAOYSA-N 2-bromo-3,4,5,6-tetrafluorobenzenesulfonyl chloride Chemical compound FC1=C(F)C(F)=C(S(Cl)(=O)=O)C(Br)=C1F CUBSXTAOVAEONH-UHFFFAOYSA-N 0.000 description 3
- JVGLQWNQRHPZMB-UHFFFAOYSA-N 2-bromo-3,4,5-trifluorobenzenesulfonyl chloride Chemical compound FC1=CC(S(Cl)(=O)=O)=C(Br)C(F)=C1F JVGLQWNQRHPZMB-UHFFFAOYSA-N 0.000 description 3
- SLXGUUYOJAEVJS-UHFFFAOYSA-N 3,4,5-trifluoro-n-(3-hydroxy-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(O)C(OC)=CC=C1NS(=O)(=O)C1=CC(F)=C(F)C(F)=C1 SLXGUUYOJAEVJS-UHFFFAOYSA-N 0.000 description 3
- VNGDFXNFUBUXKA-UHFFFAOYSA-N 3,4,5-trifluoro-n-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=CC(F)=C(F)C(F)=C1 VNGDFXNFUBUXKA-UHFFFAOYSA-N 0.000 description 3
- PTAPWFLHAVOUHJ-UHFFFAOYSA-N 3,5-dichloro-2,4,6-trifluoro-n-(3-hydroxy-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(O)C(OC)=CC=C1NS(=O)(=O)C1=C(F)C(Cl)=C(F)C(Cl)=C1F PTAPWFLHAVOUHJ-UHFFFAOYSA-N 0.000 description 3
- XDYKWPNNTGMVKV-UHFFFAOYSA-N 3,5-dichloro-2,4,6-trifluorobenzenesulfonyl chloride Chemical compound FC1=C(Cl)C(F)=C(S(Cl)(=O)=O)C(F)=C1Cl XDYKWPNNTGMVKV-UHFFFAOYSA-N 0.000 description 3
- BBBAYGJTRRZKTC-UHFFFAOYSA-N 4-bromo-2,3,5,6-tetrafluoro-n-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(Br)C(F)=C1F BBBAYGJTRRZKTC-UHFFFAOYSA-N 0.000 description 3
- MEZPAKLVSGAERH-UHFFFAOYSA-N 4-chloro-2,3,5,6-tetrafluoro-n-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(Cl)C(F)=C1F MEZPAKLVSGAERH-UHFFFAOYSA-N 0.000 description 3
- XMRWHKXOGDGNHJ-UHFFFAOYSA-N 4-fluoro-n-(4-methoxyphenyl)-3-nitrobenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=CC=C(F)C([N+]([O-])=O)=C1 XMRWHKXOGDGNHJ-UHFFFAOYSA-N 0.000 description 3
- JPWPTHYAXFJZEX-UHFFFAOYSA-N 5-bromo-2,3,4-trifluorobenzenesulfonyl chloride Chemical compound FC1=C(F)C(Br)=CC(S(Cl)(=O)=O)=C1F JPWPTHYAXFJZEX-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 150000003456 sulfonamides Chemical class 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 2
- PCGXALSKZRHXOX-UHFFFAOYSA-N 2,3,4,5-tetrafluoro-n-(3-fluoro-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(F)C(OC)=CC=C1NS(=O)(=O)C1=CC(F)=C(F)C(F)=C1F PCGXALSKZRHXOX-UHFFFAOYSA-N 0.000 description 2
- WCPZRJPXQPEWOJ-UHFFFAOYSA-N 2,3,4,6-tetrafluoro-5-[(3-fluoro-4-methoxyphenyl)sulfamoyl]benzoic acid Chemical compound C1=C(F)C(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(F)C(C(O)=O)=C1F WCPZRJPXQPEWOJ-UHFFFAOYSA-N 0.000 description 2
- OMAJARUXDQCLTO-UHFFFAOYSA-N 2,3,4,6-tetrafluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfamoyl]benzoic acid Chemical compound C1=C(O)C(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(F)C(C(O)=O)=C1F OMAJARUXDQCLTO-UHFFFAOYSA-N 0.000 description 2
- FBAXNZWDMOJIFL-UHFFFAOYSA-N 2,3,4,6-tetrafluoro-5-[(4-methoxyphenyl)sulfamoyl]benzoic acid Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(F)C(C(O)=O)=C1F FBAXNZWDMOJIFL-UHFFFAOYSA-N 0.000 description 2
- ILLJRJUJVYZWEZ-UHFFFAOYSA-N 2,3,4,6-tetrafluoro-n-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=C(F)C=C(F)C(F)=C1F ILLJRJUJVYZWEZ-UHFFFAOYSA-N 0.000 description 2
- KWGOMCGSAAGBBK-UHFFFAOYSA-N 2,3,4-trifluoro-5-[(3-fluoro-4-methoxyphenyl)sulfamoyl]benzoic acid Chemical compound C1=C(F)C(OC)=CC=C1NS(=O)(=O)C1=CC(C(O)=O)=C(F)C(F)=C1F KWGOMCGSAAGBBK-UHFFFAOYSA-N 0.000 description 2
- XIKMYDYIFMIMQB-UHFFFAOYSA-N 2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfamoyl]benzoic acid Chemical compound C1=C(O)C(OC)=CC=C1NS(=O)(=O)C1=CC(C(O)=O)=C(F)C(F)=C1F XIKMYDYIFMIMQB-UHFFFAOYSA-N 0.000 description 2
- UHYIENZZAVUHSX-UHFFFAOYSA-N 2,3,4-trifluoro-5-[(4-methoxyphenyl)sulfamoyl]benzoic acid Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=CC(C(O)=O)=C(F)C(F)=C1F UHYIENZZAVUHSX-UHFFFAOYSA-N 0.000 description 2
- ZEGWRALLTDGCBL-UHFFFAOYSA-N 2,3,4-trifluoro-n-(3-hydroxy-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(O)C(OC)=CC=C1NS(=O)(=O)C1=CC=C(F)C(F)=C1F ZEGWRALLTDGCBL-UHFFFAOYSA-N 0.000 description 2
- LBSHLAUHXYJGJZ-UHFFFAOYSA-N 2,3,4-trifluoro-n-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=CC=C(F)C(F)=C1F LBSHLAUHXYJGJZ-UHFFFAOYSA-N 0.000 description 2
- XINCBNCLCIQIJM-UHFFFAOYSA-N 2,4,6-trifluorobenzenesulfonyl chloride Chemical compound FC1=CC(F)=C(S(Cl)(=O)=O)C(F)=C1 XINCBNCLCIQIJM-UHFFFAOYSA-N 0.000 description 2
- KZMVSDGUYVLTTH-UHFFFAOYSA-N 2-bromo-3,4,5,6-tetrafluoro-n-(3-fluoro-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(F)C(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(F)C(F)=C1Br KZMVSDGUYVLTTH-UHFFFAOYSA-N 0.000 description 2
- GGPCFSHQXLVTSO-UHFFFAOYSA-N 2-bromo-3,4,5,6-tetrafluoro-n-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(F)C(F)=C1Br GGPCFSHQXLVTSO-UHFFFAOYSA-N 0.000 description 2
- GVUZWQXNPLQRKC-UHFFFAOYSA-N 2-bromo-3,4,5,6-tetrafluorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C(F)C(F)=C(F)C(F)=C1Br GVUZWQXNPLQRKC-UHFFFAOYSA-N 0.000 description 2
- GRBJVYGMFKVYOF-UHFFFAOYSA-N 3,4,5-trifluoro-n-(3-fluoro-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(F)C(OC)=CC=C1NS(=O)(=O)C1=CC(F)=C(F)C(F)=C1 GRBJVYGMFKVYOF-UHFFFAOYSA-N 0.000 description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 239000003790 pyrimidine antagonist Substances 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000012991 xanthate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the field of the invention is substituted benzene derivatives and analogs and their use as pharmacologically active agents capable of inhibiting abnormal cell proliferation.
- a number of human diseases stem from processes of uncontrolled or abnormal cellular proliferation. Most prevalent among these is cancer, a generic name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neoplastic malignancies affect, with various degrees of prevalence, every tissue and organ in the body. A multitude of therapeutic agents have been developed over the past few decades for the treatment of various types of cancer.
- anticancer agents include: DNA-alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine antagonist), microtubule disruptors (e.g., vincristine, vinblastine, paclitaxel), DNA intercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormone therapy (e.g., tamoxifen, flutamide).
- DNA-alkylating agents e.g., cyclophosphamide, ifosfamide
- antimetabolites e.g., methotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine antagonist
- microtubule disruptors e.g., vincristine, vinblastine, paclitaxel
- DNA intercalators e.
- Psoriasis a common chronic skin disease characterized by the presence of dry scales and plaques, is generally thought to be the result of abnormal cell proliferation. The disease results from hyperproliferation of the epidermis and incomplete differentiation of keratinocytes. Psoriasis often involves the scalp, elbows, knees, back, buttocks, nails, eyebrows, and genital regions, and may range in severity from mild to extremely debilitating, resulting in psoriatic arthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. No therapeutic cure exists for psoriasis.
- Milder cases are often treated with topical corticosteroids, but more severe cases may be treated with antiproliferative agents, such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea, and the microtubule disrupter colchicine.
- antiproliferative agents such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea, and the microtubule disrupter colchicine.
- Other diseases associated with an abnormally high level of cellular proliferation include restenosis, where vascular smooth muscle cells are involved, inflammatory disease states (for example US-A-6 482 860), where endothelial cells, inflammatory cells and glomerular cells are involved, myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endothelial cells are involved, infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved, and the like. Infectious and parasitic agents per se (e.g. bacteria, trypanosomes, fungi, etc) are also subject to selective proliferative control using the subject compositions and compounds.
- inflammatory disease states for example US-A-6 482 860
- endothelial cells, inflammatory cells and glomerular cells are involved myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endo
- An object of the present invention is to provide compounds which directly or indirectly are toxic to actively dividing cells and are useful in the treatment of cancer or cancerous conditions, viral and bacterial infections, vascular restenosis, inflammatory diseases, autoimmune diseases, and psoriasis.
- a further object of the present invention is to provide therapeutic compositions for treating said conditions.
- Still further objects are to provide methods for killing actively proliferating cells, such as cancerous, bacterial, or epithelial cells, and treating all types of cancers, infections, inflammatory, and generally proliferative conditions.
- a further object is to provide methods for treating other medical conditions characterized by the presence of rapidly proliferating cells, such as psoriasis and other skin disorders.
- the invention provides methods and compositions relating to novel substituted benzene derivatives and analogs and their use as pharmacologically active agents.
- the compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, bacterial infections, and psoriasis, or as lead compounds for the development of such agents.
- the invention provides use of a compound which is a substance of Formula II: or a pharmaceutically acceptable salt thereof, wherein:
- the invention provides a compound having the Formula I: or a pharmaceutically acceptable salt thereof, wherein:
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:
- the invention provides the use of a compound having the Formula I: or a pharmaceutically acceptable salt thereof, wherein:
- Preferred embodiments of the invention include the use of a compound of Formula II, wherein R 3 is halogen, NO 2 , OCF 3 , S(O)-Ar, SO 2 -R 8 , SO 2 -Ar, N 3 , N(R 6 )-SO 2 -CF 3 , N(R 6 )-SO 2 -R 8 , N(R 6 )-SO 2 -Ar, N(R 6 )-CO-(R 8 ), N(R 6 )-CO-Ar, N[CO-R 8 ] 2 , N(R 8 ) 3 + , N(R 8 ) 2 (Ar) + , O-SO 2 -Ar, O-SO 2 -R 8 , O-CO-R 8 , O-CO-Ar, O-Ar, O-R 8 , or O-CO-CF 3 , wherein R 6 is hydrogen, (C1-C6) alkyl or (C1-C6) heteroalkyl.
- R 2 and R 4 are independently selected from hydrogen, F, Cl, Br, OCF 3 , CF 3 , NO 2 , CN and CO 2 -R.
- R 3 is halogen or OCF 3 or wherein R 3 is selected from NO 2 , N 3 , O-SO 2 -Ar, O-SO 2 -R 8 and SO 2 -Ar or wherein R 3 is selected from N(R 6 )-SO 2 -CF 3 , N(R 6 )-SO 2 -(R 8 ), N(R 6 )-SO 2 -Ar, N(R 6 )-CO-(R 8 ), N(R 6 )-CO-Ar, N[CO-R 8 ] 2 and O-CO-CF 3 .
- the invention provides a compound of Formula I or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I, wherein R 3 is OCF 3 or wherein R 3 is F, Cl or Br. Also preferred is a compound of Formula I, wherein R 4 is selected from hydrogen, F, Cl, Br, OCF 3 , CF 3 , NO 2 and CN or wherein R 2 is selected from NO 2 , CN and CO 2 -R 8 or wherein R 4 is selected from F, Cl, Br, OCF 3 and CF 3 .
- alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons) and includes straight or branched chain groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, see-butyl, homologs and isomers of n-pentyl, n-hexyl, 2-methylpentyl, 1,5-dimethylhexyl, 1-methyl-4-isopropylhexyl and the like.
- alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
- a "lower alkyl” is a shorter chain alkyl, generally having six or fewer carbon atoms.
- heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
- Examples include -O-CH 2 -CH 2 -CH 3 , -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -CH 2 -OH, -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 -S(O)-CH 3 , -O-CH 2 -CH 2 -CH 2 -NH-CH 3 , and -CH 2 -CH 2 -S(O) 2 -CH 3 .
- heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-.
- cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively.
- Examples of cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like.
- heterocycloalkyl examples include 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrafuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
- alkenyl employed alone or in combination with other terms means, unless otherwise stated, a stable straight chain or branched monounsaturated or diunsaturated hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers.
- heteroalkenyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or diunsaturated hydrocarbon radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quarternized. Up to two heteroatoms may be placed consecutively.
- alkynyl employed alone or in combination with other terms means, unless otherwise stated, a stable straight chain or branched hydrocarbon group having the stated number of carbon atoms, and containing one or two carbon-carbon triple bonds, such as ethynyl, 1- and 3-propynyl, 4-but-1-ynyl, and the higher homologs and isomers.
- alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higher homologs and isomers.
- halo or halogen by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
- aryl employed alone or in combination with other terms means, unless otherwise stated, a phenyl, 1-naphthyl, or 2-naphthyl group.
- the maximal number of substituents allowed on each one of these ring systems is five, seven, and seven, respectively. Substituents are selected from the group of acceptable substituents listed above.
- heteroaryl by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or bicyclic heterocyclic aromatic ring system which consists of from four to ten carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom(s) may optionally be quaternized.
- the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom which affords a chemically stable structure.
- the heterocyclic system may be substituted or unsubstituted with one to four substituents independently selected from the list of acceptable aromatic substituents listed above.
- heterocycles examples include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
- a “leaving group” is defined as any substituent on an aromatic ring that can be displaced by a heteroatom nucleophile (particularly a sulfhydryl group) under a variety of conditions of solvent, pH, ionic strength and temperature.
- the chemical reaction in which an aromatic leaving group is replaced by a nucleophile is known as an "aromatic substitution" or “S N Ar” reaction. Reactions of the S N Ar type are often called addition-elimination reactions and proceed in solution through a ⁇ -complex called the Meisenheimer complex. Depending on the nature of the leaving group the Meisenheimer complex can be an intermediate or a transition state.
- leaving groups include: fluoro, chloro, bromo, iodo, nitro, trifluoromethoxy, Ph-S(O)-, azido, CF 3 SO 2 NH-, PhSO 2 NH-, trimethylammonium, PhOSO 2 -, and trifluoroacetate.
- the overall free energy for the S N Ar reaction is obtained by adding the gas phase and solution free energy profiles. Using this approach, one can calculate the free energy barrier for specific componds of Formula I as they undergo S N Ar reaction with thiolate ions in aqueous solution.
- Zheng and Ornstein J . Am. Chem. Soc., 1997 , 119 , 648-655 have developed and applied this method for the evaluation of the S N Ar reaction between 1-chloro-2,4-dinitrobenzene and a thiolate ion, and found that, at the HF/6-31+G** level of theory, the theoretical and experimental energy values are in good agreement.
- Pharmaceutically acceptable salts of the compounds of Formula I include salts of these compounds with relatively nontoxic acids or bases, depending on the particular substituents found on specific compounds of Formula I.
- base addition salts can be obtained by contacting the neutral form of compound I with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
- acid addition salts can be obtained by contacting the neutral form of compound I with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monahydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
- inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monahydrogensulfuric, hydriodic, or
- salts of amino acids such as arginate and the like, and salts of organic acids like gluconic or galactunoric acids and the like (see, for example, Berge, S.M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science , 1977 , 66 , 1-19).
- Certain specific compounds of Formula I contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
- Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
- the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
- Certain compounds of the present invention possess asymmetric carbon atoms (optical centers); the racemates, diastereomers, and individual isomers are all intended to be encompassed within the scope of the present invention.
- the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
- Preferred compounds and compositions of this embodiment of the invention have specific pharmacological properties.
- Examples of compounds useful in this embodiment of the invention include:
- One method for making compounds of the invention and related compounds involves combining an appropriate sulfonyl chloride (iii) with an appropriate aniline (iv), as outlined in Scheme 1, to yield a sulfonamide (v).
- the necessary sulfonyl chlorides (iii) can be prepared by sulfonation of the appropriately substituted aromatic compounds (i) with fuming sulfuric acid, followed by treatment with a chlorinating agent, such as PCl 5 , POCl 3 and the like, to afford the corresponding sulfonyl chlorides (iii), (Scheme 1).
- a chlorinating agent such as PCl 5 , POCl 3 and the like
- the sulfonamides contain certain groups, such as chloro or bromo, these groups can be catalytically reduced to produce yet other analogous sulfonamides (vi).
- the desired sulfonyl chlorides (iii) are prepared from their corresponding anilines (vii) by dissolving the aniline in an acidic aqueous solution, such as HCl and the like, followed by addition of an aqueous solution of sodium nitrite at a temperature below ambient temperature, typically between -20 and +5 °C.
- the resulting mixture, containing the desired diazonium salt is then added to a saturated solution of sulfur dioxide in glacial acetic acid containing cuprous chloride, at a temperature between -10 and +10 °C, to yield the corresponding sulfonyl chloride (iii) (see Scheme 3).
- the desired sulfonyl chlorides (iii) can also be prepared by oxidation of the respective thiophenols (ix) with chlorine and hydrogen peroxide in acetic acid as shown in Scheme 4.
- the sulphinamides described in this patent can be synthesized by reaction of the desired sulphinyl chlorides (xiii) with the appropriate amine (iv), as shown in Scheme 5.
- the necessary sulphinyl chlorides (xiii) are prepared by metal-halogen exchange reaction on the appropriate aryl bromides (x), chlorides or iodides, with an alkyllithium reagent such as butyllithium, or with magnesium metal, followed by treatment of the resulting aryl organometallic compounds (xi) with sulfur dioxide affords the lithium sulfinates (xii) that can be further reacted with thionyl chloride to afford the desired sulphinyl chlorides (xiii).
- the sulfoxides (xviii) and sulfones (xix) described in this patent can be prepared by reaction of the desired substituted thiophenols (xv) with the derivatized benzylic halides (xvi) to yield the corresponding sulfides (xvii), which can be oxidized to the corresponding sulfoxides (xviii) or sulfones according to Scheme 6.
- the necessary thiophenols (xv) can be prepared from the starting substituted anilines (vii) by diazotization, followed by treatment with sodium sulfide (Scheme 6).
- the thiophenols (xv) can be prepared by treatment of the diazonium salts (viii) with potassium ethyl xanthate, followed by saponification of the resulting xanthates (xx), as shown in Scheme 7.
- Other alternate methods for the synthesis of the desired substituted thiophenols (xv) are described in the chemical literature and should be well known to individuals versed in the art of organic synthesis.
- Some of the compounds of Formula I may exist as stereoisomers, and the invention includes all active stereoisomeric forms of these compounds.
- optically active isomers such compounds may be obtained from corresponding optically active precursors using the procedures described above or by resolving racemic mixtures. The resolution may be carried out using various techniques such as chromatography, repeated recrystallization of derived asymmetric salts, or derivatization, which techniques are well known to those of ordinary skill in the art.
- the compounds of the invention may be labeled in a variety of ways.
- the compounds may contain radioactive isotopes such as, for example, 3 H (tritium) and 14 C (carbon-14).
- the compounds may be advantageously joined, covalently or noncovalently, directly or through a linker molecule, to a wide variety of other compounds, which may provide pro-drugs or function as carriers, labels, adjuvents, coactivators, stabilizers, etc.
- labeled and joined compounds are contemplated within the present invention.
- the subject compounds and compositions were demonstrated to have pharmacological activity in in vitro and in vivo assays, e.g., they are capable of specifically modulating a cellular physiology to reduce an associated pathology or provide or enhance a prophylaxis.
- Preferred compounds and compositions of the invention display specific toxicity to various types of cells. Certain compounds and compositions of the present invention exert their cytotoxic effects by interacting with cellular tubulin. For certain preferred compounds and compositions of the present invention, that interaction is covalent and irreversible. Compounds and compositions may be evaluated in vitro for their ability to inhibit cell growth, for example, as described in Ahmed et al. ( J . Immunol. Methods 1994, 170 , 211). Established animal models to evaluate antiproliferative effects of compounds are known in the art. For example, compounds can be evaluated for their ability to inhibit the growth of human tumors grafted into immunodeficient mice using methodology similar to that described by Rygaard and Povlsen ( Acta Pathol . Microbiol. Scand 1969, 77 , 758) and Giovanella and Fogh ( Adv. Cancer Res. 1985, 44 , 69).
- the invention provides methods of using the subject compounds and compositions to treat disease or provide medicinal prophylaxis, to slow down and/or reduce the growth of tumors, etc. These methods generally involve contacting the cell with or administering to the host an effective amount of the subject compounds or pharmaceutically acceptable compositions.
- the compounds used in the invention may be conjugated to targeting molecules which preferentially direct the compound to a targeted cell.
- compositions and compounds of the invention and the pharmaceutically acceptable salts thereof can be administered in any effective way such as via oral, parenteral (such as intraverous or intramuscular) or topical routes.
- the compounds are administered in dosages ranging from about 2 mg up to about 2,000 mg per day, although variations will necessarily occur depending on the disease target, the patient, and the route of administration.
- Preferred dosages are administered orally in the range of about 0.05 mg/kg to about 20 mg/kg, more preferably in the range of about 0.05 mg/kg to about 2 mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mg per kg of body weight per day.
- the invention provides the subject compounds combined with a pharmaceutically acceptable excipient such as sterile saline or other medium, water, gelatin, an oil, etc. to form pharmaceutically acceptable compositions.
- a pharmaceutically acceptable excipient such as sterile saline or other medium, water, gelatin, an oil, etc.
- the compositions and/or compounds may be administered alone or in combination with any convenient carrier, diluent, etc. and such administration may be provided in single or multiple dosages.
- Useful carriers include solid, semi-solid or liquid media including water and non-toxic organic solvents.
- the invention provides the subject compounds in the form of a pro-drug, which can be metabolically converted to the subject compound by the recipient host.
- a pro-drug which can be metabolically converted to the subject compound by the recipient host.
- compositions may be provided in any convenient form including tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, suppositories, etc.
- compositions in pharmaceutically acceptable dosage units or in bulk, may be incorporated into a wide variety of containers.
- dosage units may be included in a variety of containers including capsules, pills, etc.
- compositions may be advantageously combined and/or used in combination with other antiproliferative therapeutic or prophylactic agents such as antineoproliferative, chemotherapeutic or cytotoxic agents, different from the subject compounds.
- antiproliferative therapeutic or prophylactic agents such as antineoproliferative, chemotherapeutic or cytotoxic agents, different from the subject compounds.
- administration in conjunction with the subject compositions enhances the efficacy of such agents.
- Examplary antiproliferative agents include cyclophosphamide, methotrexate, adriamycin, cisplatin, daunomycin, vincristine, vinblastine, vinarelbine, paclitaxel, docetaxel, tamoxifen, flutamide, hydroxyurea, and mixtures thereof.
- the compounds and compositions also find use in a variety of in vitro and in vivo assays, including diagnostic assays. In certain assays and in in vivo distribution studies, it is desirable to used labeled versions of the subject compounds and compositions, e.g. radioligand displacement assays. Accordingly, the invention provides the subject compounds and compositions comprising a detectable label, which may be spectroscopic (e.g. fluorescent), radioactive, etc.
- a detectable label which may be spectroscopic (e.g. fluorescent), radioactive, etc.
- 1,3-Dichloro-2,4,6-trifluorobenzene (5.0 g, 25 mmol) and chlorosulfonic acid (10.0 ml, 150 mmol) were mixed at ambient temperature under a nitrogen atmosphere and the reaction was heated at 80 °C for 24 h. The mixture was then allowed to cool to ambient temperature and was poured onto 12 g of crushed ice. The product was extracted with diethyl ether, dried over MgSO 4 , and evaporated to produce 4.9 g of the title compound, which was used without further purification. MS (EI): 300 (30, M + ), 298 (28), 263 (100), 199 (80).
- Example D 5-Bromo-2,3,4-trifluorophenylsulfonyl chloride (Example D) and 2-Bromo-3,4,5-trifluorophenylsulfonyl chloride (Example E).
- the title compounds were obtained as a mixture from 1-bromo-2,3,4-trifluorobenzene by a method similar to that used in Example B.
- Example F The title compound was prepared in a manner similar to that described in Example 1 by replacing p -anisidine with 3-hydroxy-4-methoxyaniline and replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 2-bromo-3,4,5,6-tetrafluorophenylsulfonyl chloride (Example F).
- Example F The title compound was prepared in a manner similar to that described in Example I by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 2-bromo-3,4,5,6-tetrafluorophenylsulfonyl chloride (Example F).
- Example G The title compound was prepared in a manner similar to that described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 3-bromo-2,4,5,6-tetrafluorophenylsulfonyl chloride (Example G).
- Example H The title compound was prepared in a manner similar to that described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 4-bromo-2,3,5,6-tetrafluorophenylsulfonyl chloride (Example H).
- Example B The title compound was prepared in a manner similar to that described in Example 1 by replacing p -anisidine with 3-hydroxy-4-methoxyaniline and replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 3,5-dichloro-2,4,6-trifluorophenylsulfonyl chloride (Example B).
- Example 10 1-Bromo-2,3,4-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzene (Example 10) and 1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene (Example 11) were prepared in a manner'similar to that described in Example I by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with a mixture of 5-bromo-2,3,4-trifluorophenylsulfonyl chloride (Example D) and 2-bromo-3,4,5-trifluorophenylsulfonyl chloride (Example E).
- Example 12 1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene (Example 12) and 1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene (Example 13) were prepared in a manner similar to that described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with a mixture of 5-bromo-2,3,4-trifluorophenylsulfonyl chloride (Example D) and 2-bromo-3,4,5-trifluorophenylsulfonyl chloride (Example E) and replacing p -anisidine with 3-hydroxy-4-methoxyaniline.
- Example C The title compound was prepared in a manner similar to that described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 2,4,6-trifluorophenylsulfonyl chloride (Example C).
- 1 H-NMR (CDCl 3 ): ⁇ 7.08 (2H, dd, J 9.0 and 2.0 Hz), 6.8-6.7 (5H, m), 3.75 (3H, s).
- Example 13 The title compound was prepared in a manner similar to that described in Example 19 by replacing 1-bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzene with 1-bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene (Example 13).
- HeLa cells an immortal cell line derived from a human cervical carcinoma commonly used to evaluate the cytotoxicity of potential therapeutic agents.
- the following data reflect the cytotoxicity of selected examples of the present invention.
- the values given represent the concentration of test compound required to inhibit by 50% the uptake of Alamar Blue (Biosource International, Camarillo, CA) by HelA cell cultures, which correlates directly with the overall levels of cellular metabolism in the culture, and is generally accepted as an appropriate marker of cell growth.
- the test was conducted according to the method of Ahmed et al. ( J . Immunol. Methods 1994 , 170 , 211).
- Example 2 0.15
- Example 3 0.05
- Example 4 0.15
- Example 5 0.15
- Example 6 5.0
- Example 7 1.5
- Example 8 0.15
- Example 9 0.05
- Example 10 0.5
- Example 11 0.5
- Example 17 1.5
- Example 19 5.0
- Example 20 0.5
- Example 21 0.15
- Example 22 5.0
- Example 23 1.5
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Claims (25)
- Verwendung einer Verbindung, die eine Substanz der Formel II: oder ein pharmazeutisch annehmbares Salz davon ist, wobei
der Index n den Wert 2 hat;
R1, R2, R4 und R5 unabhängig voneinander aus Wasserstoff, (C1-C6)-Alkyl, Halogen, OCF3, CF3, NO2, CN und CO2-R8 ausgewählt werden;
R3 für eine austretende Gruppe steht;
Y für-NH- steht;
und Ar eine gegebenenfalls substituierte Aryl- oder Heteroarylgruppe ist, bei der die Substituenten unabhängig voneinander aus OH, Halogen, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, (C1-C6)-Alkyl und (C1-C6)-Alkoxy ausgewählt werden;
wobei R8 ausgewählt wird aus (C1-C6)-Alkyl oder (C1-C6)-Heteroalkyl, bei der Herstellung eines Medikaments zur Verwendung bei der Behandlung oder Vermeidung eines Krankheitszustands, der durch ein abnormal hohes Niveau der Zellwucherung gekennzeichnet ist. - Verwendung nach Anspruch 1, wobei R3 für Halogen, NO2, OCF3, S(O)-Ar, SO2-R8, SO2-Ar, N3, N(R6)-SO2-CF3, N(R6)-SO2-R8, N(R6)-SO2-Ar, N(R6)-CO-(R8), N(R6)-CO-Ar, N[CO-R8]2, N(R8)3 +, N(R8)2(Ar)+, O-SO2-Ar, O-SO2-R8, O-CO-R8, O-CO-Ar, O-Ar, O-R8 oder O-CO-CF3 steht, wobei R6 für Wasserstoff, (C1-C6)-Alkyl oder (C1-C6)-Heteroalkyl steht.
- Verwendung nach Anspruch 2, wobei R2 und R4 unabhängig voneinander aus Wasserstoff, F, Cl, Br, OCF3, CF3, NO2, CN und CO2-R8 ausgewählt werden.
- Verwendung nach Anspruch 3, wobei R3 für Halogen oder OCF3 steht.
- Verwendung nach Anspruch 3, wobei R3 aus NO2, N3, O-SO2-Ar, O-SO2-R8 und SO2-Ar ausgewählt wird.
- Verwendung nach Anspruch 3, wobei R3 aus N(R6)-SO2-CF3, N(R6)-SO2-(R8), N(R6)-SO2-Ar, N(R6)-CO-(R8), N(R6)-CO-Ar, N[CO-R8]2 und O-CO-CF3 ausgewählt wird.
- Verbindung der Formel I: oder eines pharmazeutisch annehmbaren Salzes davon, wobei
der Index n den Wert 2 hat;
R1 und R5 unabhängig voneinander aus Wasserstoff, F, Cl, Br, OCF3, CF3, NO2 und CN ausgewählt werden;
R2 aus NO2, CN und CO2-R8 ausgewählt wird;
R3 aus F, Cl, Br und OCF3 ausgewählt wird;
R4 aus Wasserstoff, F, Cl, Br, OCF3, CF3, NO2, CN und CO2-R8 ausgewählt wird; Y für -NH- steht;
wobei R8 für (C1-C6)-Alkyl steht;
und Ar eine substituierte oder unsubstituierte Phenylgruppe ist;
wobei die Substituenten unabhängig voneinander aus OH, Halogen, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, (C1-C6)-Alkyl und (C1-C6)-Alkoxy ausgewählt werden;
mit den folgenden Bedingungen:wenn R1 = R3 = F, R4 = Cl und Y = -NH- ist, dann ist Ar ein anderer Ring als unsubstituiertes Phenyl;wenn R1 = R3 = R5 = Br und Y = -NH- ist, dann ist Ar ein anderer Ring als mit (C1-C6)-Alkyl substituiertes Phenyl;wenn R1 = R3 = R5 = Cl, Y = -NH- und R9 = H oder Methyl ist, dann ist Ar ein Phenylring, der mit 1-4 Gruppen, die unabhängig voneinander aus Halogen, OH, OR', NH2, NHR' und NR'R" ausgewählt werden, substituiert ist;wenn R1 = R3 = Cl ist, dann darf R4 nicht Chlor enthalten, - Verbindung nach Anspruch 7, wobei R3 für OCF3 steht.
- Verbindung nach Anspruch 7, wobei R3 für F, Cl oder Br steht.
- Verbindung nach Anspruch 9, wobei R4 aus Wasserstoff, F, Cl, Br, OCF3 CF3, NO2 und CN ausgewählt wird.
- Verbindung nach Anspruch 8 oder 9, wobei R2 aus NO2, CN und CO2-R8 ausgewählt wird.
- Verbindung nach Anspruch 8 oder 9, wobei R4 aus F, Cl, Br, OCF3 und CF3 ausgewählt wird.
- Pharmazeutische Zubereitung mit pharmazeutisch annehmbarem Arzneimittelträger und einer Verbindung der Formel I: oder eines pharmazeutisch annehmbaren Salzes davon, wobei
der Index n den Wert 2 hat;
R1 und R5 unabhängig voneinander aus Wasserstoff, F, Cl, Br, OCF3, CF3, NO2 und CN ausgewählt werden;
R2 aus NO2, CN und CO2-R8 ausgewählt wird;
R3 aus F, Cl, Br und OCF3 ausgewählt wird;
R4 aus Wasserstoff, F, Cl, Br, OCF3, CF3, NO2, CN und CO2-R8 ausgewählt wird; Y für -NH- steht;
wobei R8 aus (C1-C6)-Alkyl ausgewählt wird;
und Ar eine substituierte oder unsubstituierte Phenylgruppe ist;
wobei die Substituenten unabhängig voneinander aus OH, Halogen, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, (C1-C6)-Alkyl und (C1-C6)-Alkoxy ausgewählt werden;
mit den folgenden Bedingungen:wenn R1 = R3 = R5 =Cl, Y = -NH- und R9 = H oder Methyl ist, dann ist Ar ein Phenylring, der mit 1-4 Gruppen, die unabhängig voneinander aus Halogen, OH, OR', NH2, NHR' und NR'R" ausgewählt sind, substituiert ist; undwenn R1 = R3 = Cl ist, dann darf R4 nicht Chlor enthalten. - Zubereitung nach Anspruch 13, wobei R3 für OCF3 steht.
- Zubereitung nach Anspruch 13, wobei R3 für F, Cl oder Br steht.
- Zubereitung nach Anspruch 15, wobei R4 aus Wasserstoff, F, Cl, Br, OCF3, CF3, NO2 und CN ausgewählt wird.
- Zubereitung nach Anspruch 14 oder 15, wobei R2 aus NO2, CN und CO2-R8 ausgewählt wird.
- Zubereitung nach Anspruch 14 oder 15, wobei R4 aus F, Cl, Br, OCF3 und CF3 ausgewählt wird.
- Verwendung einer Verbindung nach einem der Ansprüche 7 bis 12 bei der Herstellung eines Medikaments zur Verwendung bei der Behandlung oder Verhinderung eines Krankheitszustands, der durch ein abnormal hohes Niveau der Zellwucherung gekennzeichnet ist.
- Verwendung nach einem der Ansprüche 1 bis 6 und 19, wobei der proliferative Krankheitszustand Krebs oder ein krebsartiger Zustand, eine Infektion durch einen Mikroorganismus, Schuppenflechte oder Gefäßrestenose ist.
- Verwendung nach einem der Ansprüche 1 bis 6 und 19 bis 20, wobei das Medikament in Verbindung mit einer therapeutisch wirksamen Menge eines antineoproliferativen, chemotherapeutischen oder cytotoxischen Mittels, das nicht durch Formel I oder Formel II dargestellt ist, verabreicht wird.
- Verwendung nach einem der Ansprüche 1 bis 6 und 19 bis 21, wobei die Verbindung als Pro-Pharmakon verabreicht wird.
- Verwendung nach einem der Ansprüche 1 bis 6 und 19 bis 22, wobei die Verbindung mit einem zielenden Molekül konjugiert wird, das die Verbindung bevorzugt zu einer Zielzelle hinlenkt.
- Verwendung nach einem der Ansprüche 1 bis 6 und 19 bis 23, wobei das Medikament oral verabreicht wird.
- Verwendung nach einem der Ansprüche 1 bis 6 und 19 bis 23, wobei das Medikament intravenös oder intramuskulär verabreicht wird.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK98939384T DK1005453T3 (da) | 1998-08-13 | 1998-08-13 | Substituerede benzenforbindelser som antiproliferative sænkende midler |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US917025 | 1997-08-22 | ||
US08/917,025 US6284923B1 (en) | 1997-08-22 | 1997-08-22 | Substituted benzene compounds as antiproliferative and cholesterol lowering action |
PCT/US1998/016781 WO1999010320A1 (en) | 1997-08-22 | 1998-08-13 | Substituted benzene compounds as antiproliferative and cholesterol lowering agents |
Publications (2)
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EP1005453A1 EP1005453A1 (de) | 2000-06-07 |
EP1005453B1 true EP1005453B1 (de) | 2004-10-27 |
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EP98939384A Expired - Lifetime EP1005453B1 (de) | 1997-08-22 | 1998-08-13 | Substituierte benzolverbindungen als antiproliferative mittel |
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US (2) | US6284923B1 (de) |
EP (1) | EP1005453B1 (de) |
JP (1) | JP4309041B2 (de) |
AT (1) | ATE280756T1 (de) |
AU (1) | AU748826B2 (de) |
CA (1) | CA2301842C (de) |
DE (1) | DE69827267T2 (de) |
ES (1) | ES2245803T3 (de) |
PT (1) | PT1005453E (de) |
WO (1) | WO1999010320A1 (de) |
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IL127965A0 (en) * | 1996-07-19 | 1999-11-30 | Tularik Inc | Pentafluorobenzenesulfonamide derivatives analogs thereof and pharmaceutical compositions containing the same |
US6583157B2 (en) | 1998-01-29 | 2003-06-24 | Tularik Inc. | Quinolinyl and benzothiazolyl modulators |
ATE413386T1 (de) | 1998-01-29 | 2008-11-15 | Amgen Inc | Ppar-gamma modulatoren |
AU763687B2 (en) * | 1998-06-25 | 2003-07-31 | Tularik Inc. | Arylsulfonanilide phosphates |
EE200100302A (et) * | 1998-12-02 | 2002-08-15 | Pfizer Products Inc. | Meetodid ja kompositsioonid p53 perekonna valgu konformatsioonilise stabiilsuse taastamiseks |
IL147308A0 (en) * | 1999-06-30 | 2002-08-14 | Tularik Inc | Compounds for the modulation of pparγ activity and pharmaceutical compositions containing the same |
US7041691B1 (en) | 1999-06-30 | 2006-05-09 | Amgen Inc. | Compounds for the modulation of PPARγ activity |
US6306615B1 (en) | 1999-08-19 | 2001-10-23 | Tularik Inc. | Detection method for monitoring β tubulin isotype specific modification |
AU6118001A (en) | 2000-05-03 | 2001-11-12 | Tularik Inc | Combination therapeutic compositions and methods of use |
US20050250854A1 (en) * | 2000-11-03 | 2005-11-10 | Amgen Inc. | Combination therapy using pentafluorobenzenesulfonamides and antineoplastic agents |
US6822001B2 (en) | 2000-11-03 | 2004-11-23 | Tularik Inc. | Combination therapy using pentafluorobenzenesulfonamides and antineoplastic agents |
EP1402890B1 (de) * | 2001-06-08 | 2008-01-09 | Institute of Medicinal Molecular Design, Inc. | Sulfonamidderivate |
JP2003081937A (ja) * | 2001-09-07 | 2003-03-19 | Bayer Ag | ベンゼンスルホンアミド誘導体 |
US7833734B2 (en) * | 2002-11-26 | 2010-11-16 | Institute Of Virology Of The Slovak Academy Of Sciences | CA IX-specific inhibitors |
HUE028349T2 (en) * | 2002-11-26 | 2016-12-28 | Inst Virology | CAIX-specific inhibitors |
FI20055498A0 (fi) * | 2005-09-16 | 2005-09-16 | Biotie Therapies Corp | Sulfonamidijohdannaisia |
GB0526252D0 (en) * | 2005-12-22 | 2006-02-01 | Novartis Ag | Organic compounds |
CA2803118C (en) | 2010-07-09 | 2015-11-03 | Pfizer Limited | Sulfonamide derivatives as nav 1.7 inhibitors |
WO2012056319A1 (en) * | 2010-10-27 | 2012-05-03 | Dynamix Pharmaceuticals Ltd. | Sulfonamides for the modulation of pkm2 |
WO2014083384A1 (en) * | 2012-11-28 | 2014-06-05 | Stichting Dienst Landbouwkundig Onderzoek | Benzenesulfonamide compounds for somatic embryogenesis iν plants |
KR20160046836A (ko) * | 2013-08-28 | 2016-04-29 | 보르그워너 인코퍼레이티드 | 고온 밸브 축 시일 |
GB201514021D0 (en) | 2015-08-07 | 2015-09-23 | Arner Elias Set Jeno | Novel Pyridines and their use in the treatment of cancer |
WO2018146472A1 (en) | 2017-02-07 | 2018-08-16 | Oblique Therapeutics Ab | Hydrocarbylsulfonyl-substituted pyridines and their use in the treatment of cancer |
CA3051537A1 (en) | 2017-02-07 | 2018-08-16 | Oblique Therapeutics Ab | Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer |
JP2020507624A (ja) | 2017-02-07 | 2020-03-12 | オブリーク セラピューティクス アーベー | スルフィニルピリジンおよび癌の治療におけるそれらの使用 |
WO2018146471A1 (en) | 2017-02-07 | 2018-08-16 | Oblique Therapeutics Ab | Heterocyclylsulfonyl-substituted pyridines and their use in the treatment of cancer |
WO2020097408A1 (en) * | 2018-11-09 | 2020-05-14 | Nimbus Artemis, Inc. | Acly inhibitors and uses thereof |
WO2023183763A1 (en) * | 2022-03-21 | 2023-09-28 | Chemocentryx, Inc. | Cxcr6 sulfonamide compounds |
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DE2528697C2 (de) | 1975-06-27 | 1986-02-20 | Bayer Ag, 5090 Leverkusen | Verfahren zur Herstellung von Salicylaldehyden |
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1997
- 1997-08-22 US US08/917,025 patent/US6284923B1/en not_active Expired - Fee Related
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1998
- 1998-08-13 AT AT98939384T patent/ATE280756T1/de not_active IP Right Cessation
- 1998-08-13 JP JP2000507650A patent/JP4309041B2/ja not_active Expired - Fee Related
- 1998-08-13 PT PT98939384T patent/PT1005453E/pt unknown
- 1998-08-13 AU AU87824/98A patent/AU748826B2/en not_active Ceased
- 1998-08-13 DE DE69827267T patent/DE69827267T2/de not_active Expired - Lifetime
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- 1998-08-13 ES ES98939384T patent/ES2245803T3/es not_active Expired - Lifetime
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US6388131B2 (en) | 2002-05-14 |
WO1999010320A8 (en) | 1999-09-23 |
CA2301842A1 (en) | 1999-03-04 |
AU8782498A (en) | 1999-03-16 |
DE69827267T2 (de) | 2006-02-02 |
PT1005453E (pt) | 2005-02-28 |
CA2301842C (en) | 2010-04-27 |
WO1999010320A1 (en) | 1999-03-04 |
ATE280756T1 (de) | 2004-11-15 |
US20020013496A1 (en) | 2002-01-31 |
AU748826B2 (en) | 2002-06-13 |
JP4309041B2 (ja) | 2009-08-05 |
DE69827267D1 (de) | 2004-12-02 |
JP2001514167A (ja) | 2001-09-11 |
ES2245803T3 (es) | 2006-01-16 |
EP1005453A1 (de) | 2000-06-07 |
US6284923B1 (en) | 2001-09-04 |
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